Article

Changes in Brain Function of Depressed Subjects

During Treatment With Placebo

Andrew F. Leuchter, M.D.
Ian A. Cook, M.D.
Elise A. Witte, Ph.D.
Melinda Morgan, Ph.D.
Michelle Abrams, R.N.
Objective: It has been proposed that
50%–75% of the efficacy of antidepressant
medication represents the placebo effect,
since many depressed patients improve
when treated with either medication or
placebo. This study examined brain func-
tion in depressed subjects receiving either
active medication or placebo and sought
to determine whether quantitative elec-
troencephalography (QEEG) could detect
differences in brain function between
medication and placebo responders.
Both QEEG power and cordance, a new
measure that reflects cerebral perfusion
and is sensitive to the effect of antidepres-
sant medication, were examined.
Method: Fifty-one subjects with major
depression were enrolled in one of two
independent, 9-week double-blind, pla-
cebo-controlled studies in which either
fluoxetine (N=24) or venlafaxine (N=27)
was the active medication. Serial QEEG re-
cordings were performed during the
course of treatment. After 9 weeks, the
blind was broken and subjects were clas-
sified as medication responders, placebo
responders, medication nonresponders,
or placebo nonresponders.
Results: No significant pretreatment dif-
ferences in clinical or QEEG measures
were found among the four outcome
groups. Placebo responders, however,
showed a significant increase in prefron-
tal cordance starting early in treatment
that was not seen in medication respond-
ers (who showed decreased cordance) or
in medication nonresponders or placebo
nonresponders (who showed no signifi-
cant change) . There was no significant
change in QEEG power during treatment.
Conclusions: These findings suggest that
“effective” placebo treatment induces
changes in brain function that are distinct
from those associated with antidepres-
sant medication. If these results are con-
firmed, cordance may be useful for differ-
e n t i ati n g be twe e n m e di c a ti on an d
placebo responders.

(Am J Psychiatry 2002; 159:122–129)

B etween 25% and 60% of depressed patients who are

treated with placebo may have substantial reductions in
symptoms (1, 2). Depression is not unique among medical
syndromes in this respect. Other medical and psychiatric
illnesses have similarly high placebo response rates (1).
Nevertheless, the high response rate in depression has led
some to conclude that 50%–75% of the apparent efficacy
of antidepressant medication actually represents the pla-
cebo effect (3, 4).
The high placebo response rates in depression compli-
cate the development of antidepressant drugs, since effec-
tive new drugs may be abandoned if they fail to show ef-
fectiveness superior to placebo (2, 5). Efficacy that is
superior to placebo can be difficult to prove for any medi-
cal treatment, but is particularly difficult for antidepres-
sant medication because of the absence of physiologic
outcome measures. The primary measure of efficacy in
depression treatment studies remains mood ratings,
which are subject to influence from a variety of sources in-
cluding subject motivation and investigator expectations.
The pattern of change in mood ratings over time has been
proposed as an indicator to differentiate between true
drug and placebo responses (2, 6, 7). Pattern analysis can
identify subjects with poorer prognoses and placebo-type
responses, but it still relies on mood ratings and extended
observation of subjects.
Brain functional measurements show promise as a
physiologic indicator of treatment effectiveness in depres-
sion. Several studies using positron emission tomography
(PET) or single-photon emission computed tomography
have documented reductions in prefrontal cortical perfu-
sion or metabolism resulting from antidepressant medica-
tion treatment (8–12). None of these studies, however, has
compared brain function in subjects actually receiving
placebo treatment with those receiving antidepressant
medication.
In this study, we used quantitative electroencephalogra-
phy (QEEG) to compare changes in brain function during
medication and placebo treatment in subjects with major
depressive disorder. We utilized both traditional QEEG
power measures as well as cordance, a new measure that
has stronger associations with cerebral perfusion than
standard QEEG measures (13) and is sensitive to the ef-
fects of antidepressant medication (14, 15).

122 Am J Psychiatry 159:1, January 2002

 LEUCHTER, COOK, WITTE, ET AL.

TABLE 1. Characteristics of Depressed Subjects in Placebo- FIGURE 1. Electrode Montage for a Quantitative EEG Study
Controlled Studies of Fluoxetine and Venlafaxine Whose of Depressed Subjects Treated in Placebo-Controlled Anti-
Brain Activity Was Measured With Quantitative EEGa depressant Trialsa
Subjects in Placebo- Subjects in Placebo-
Controlled Study of Controlled Study of
Characteristic Fluoxetine (N=24) Venlafaxine (N=27)
Mean SD Mean SD
Fp1 Fpz Fp2
Age (years) 40.3 11.5 42.6 12.5
AF1 AF2
Hamilton Depression
Rating Scale score F7 F8
Baseline 21.8 4.2 22.4 3.1 F3 Fz F4
Final (week 8) 12.3 8.3 13.1 6.2
Total number of FC5 FC1 FC2 FC6
depressive episodes 2.3 1.1 2.0 1.3
A1 T3 C3 Cz C4 T4 A2
Ratio Ratio
CP5 CP1 CP2 CP6
Gender (male:female) 0.5:1 0.7:1
Family history Pz
P3 P4
of depression T5 T6
(positive:negative) 1:1 3:1
PO7 PO1 PO2 PO8
a Subjects were patients with major depressive episode enrolled in
one of two 9-week double-blind, placebo-controlled treatment O1 O2
Oz
studies conducted independently over a 24-month period. Doses
of active medication were 20 mg/day for fluoxetine and 150 mg/
day for venlafaxine. Subjects in the fluoxetine study did not differ
significantly in demographic or clinical characteristics from those a The montage consists of the 35 scalp electrodes from the extended
in the venlafaxine study. International 10-20 System. Absolute power values were reattrib-
uted to each individual electrode by averaging power values from
all bipolar electrode pairs sharing that electrode (e.g., for electrode
Method C3, power values from the pairs FC5-C3, FC1-C3, CP5-C3, and CP1-C3
were averaged) (18).
Subjects
Subjects were enrolled in one of two 9-week, double-blind pla- consisted of symptom evaluation (with the Hamilton depression
cebo-controlled treatment studies conducted independently scale) as well as brief sessions of supportive psychotherapy with a
over a 24-month period: the first study utilized fluoxetine, 20 mg, research nurse. These sessions consisted of 15–25 minutes of un-
(N=24) and the second, venlafaxine, 150 mg, (N=27) as the active structured counseling and assistance in problem solving. The
medication. Subjects were recruited both from community ad- sessions were mandated by the institutional review board to ad-
vertisement and from the outpatient clinics of the UCLA Neuro- dress safety concerns about dispensing placebo alone to patients
psychiatric Hospital. The UCLA institutional review board ap- with significant depression. We defined clinical response as a
proved all experimental procedures, and written informed Hamilton depression scale score ≤ 10 after 8 weeks of double-
consent was obtained after experimental procedures were ex-
blind treatment. At this time, the blind was broken, and subjects
plained fully to the subjects.
were classified as medication responders, placebo responders,
The two studies utilized identical inclusion and exclusion crite-
medication nonresponders, or placebo nonresponders. We also
ria. All subjects were adults who met DSM-IV criteria for a major
determined how early in the course of treatment each responder
depressive episode, as diagnosed with the Structured Clinical In-
had a substantial reduction in symptoms, as well as the per-
terview for DSM-IV. All subjects had Hamilton Depression Rating
sistence of their response to treatment. This pattern analysis
Scale scores ≥16 (16), and subjects were excluded if they previ-
permitted us to classify the medication responder and placebo
ously had failed treatment with the antidepressant being studied,
responder subjects as having the late, persistent pattern of symp-
if they had a history of suicidal ideation, or if they suffered from
tomatic improvement indicative of true drug response, or the
any medical illness or received any medication known to signifi-
early, nonpersistent pattern of improvement indicative of pla-
cantly affect brain function. The demographic and clinical char-
cebo response (2, 6, 7).
acteristics of the subjects in the two studies are shown in Table 1.

Experimental Procedures QEEG Techniques

After enrollment, all subjects received single-blind, placebo
lead-in treatment for 1 week; subjects who met response criteria
(Hamilton depression scale score ≤10) after this week were re-
moved from the study. The remaining 51 subjects then were ran-
domly assigned to receive 8 weeks of double-blind treatment with
either placebo or the active medication. Subjects enrolled in the
fluoxetine trial were continued at a dose of 20 mg/day for the 8
weeks; those enrolled in the venlafaxine trial began at a dose of
37.5 mg/day, increased over a week to 150 mg/day, and then con-
tinued at that dose for the remaining 7 weeks. To preserve blind-
ing, the placebo “dose” was escalated in the venlafaxine trial.
Subjects returned for monitoring sessions 2 days after random
assignment to study groups and then at weekly intervals. Sessions
QEEG data were examined from recordings performed at the
time of enrollment in the study (baseline), at the end of the 1-week
placebo lead-in, and at 2, 4, and 8 weeks after the start of double-
blind treatment. Electrodes were placed with an electrode cap
(ElectroCap, Eaton, Ohio) by using an extended International 10-
20 System with a total of 35 recording electrodes (Figure 1). Eye
movements were monitored with right infraorbital and left outer
canthus electrodes. Recordings were performed with the QND
system (Neurodata, Inc., Pasadena, Calif.) while subjects rested
with eyes closed in a maximally alert state in a sound-attenuated
room with subdued lighting. These procedures have been de-
scribed previously (13, 17, 18). Data were collected by using a Pz
reference montage and were digitized at 256 samples/channel/

Am J Psychiatry 159:1, January 2002 123

PLACEBO EFFECTS
TABLE 2. Groupings of Electrodes for Assessment of Re-
gional Quantitative EEG Activity of Depressed Subjects
Treated in Placebo-Controlled Antidepressant Trials
Region Grouping of Electrodes
Prefrontal Fp1, Fpz, Fp2
Central FC1, Cz, FC2
Temporal
Left T3, T5
Right T4, T6
Parietal
Left P3, CP1, CP5
Right P4, CP2, CP6
Occipital O1, O2, Oz
second, with a high-frequency filter of 50 Hz and a low-frequency
filter of 0.3 Hz. Data were reformatted by amplitude subtraction to
a linked-ears reference. A technician who was blinded to subject
identity, treatment condition, and clinical status reviewed the
record and selected the first 20–32 seconds of artifact-free data for
processing; this amount of data has been used by our group (13,
19) and other investigators (20) to obtain reliable frequency spec-
tra. A fast Fourier transform was used to calculate absolute power
(the intensity of energy in a frequency band in microvolts squared)
and relative power (the percentage of the total energy from all
bands concentrated in a single band) in each of four nonoverlap-
ping frequency bands, inclusive at the lower boundary of each
band (0.5–4 Hz, 4–8 Hz, 8–12 Hz, and 12–20 Hz).
In addition, for each electrode site in each of the four bands,
cordance values were calculated. Cordance is a measure derived
from QEEG power that has a moderately strong association with
cerebral perfusion (as measured by simultaneous O15 PET); this
association is superior to that seen for conventional QEEG power
measurements in each frequency band, including the alpha band
(13). Cordance is calculated with a three-step algorithm that nor-
malizes power across both electrode sites and frequency bands.
This algorithm has been defined in detail elsewhere (13) and may
be summarized as follows. First, absolute power values are reat-
tributed to each individual electrode by averaging power from all
bipolar electrode pairs sharing that electrode (Figure 1). This
electrode referencing method is similar to the Hjorth transforma-
tion, except that the current method averages power from neigh-
boring electrode pairs whereas the Hjorth transformation aver-
ages voltage amplitudes. We previously reported that electrode
referencing on the basis of power averaging provides a stronger
association between surface-measured EEG and perfusion of un-
derlying brain than either the linked-ears reference or the con-
ventional Hjorth transformation (18). Second, absolute and rela-
tive power values undergo spatial normalization within each
frequency band by means of a z score transformation, yielding z
scores for each electrode site s and frequency band f (A norm(s,f )
and Rnorm(s,f ), respectively). Third, the z-transformed absolute
and relative power scores are summed to yield cordance values
(13). (Software for performing cordance calculations is available
to academic institutions free of charge for research purposes; see
instructions at www.qeeg.npi.ucla.edu.)
For each subject over the course of treatment, we calculated
power and cordance values for individual electrodes (Figure 1). To
limit the number of statistical comparisons, we grouped subsets
of the individual electrodes into regional measures to reflect the
major brain functional areas (Table 2). QEEG power or cordance
values from electrodes in these groups were averaged together to
obtain the regional measure. We also further limited our analysis
to the theta frequency band (4–8 Hz), because our previous work
and work from other laboratories has indicated that energy in the
theta band is most strongly associated with treatment outcomes
in depression (17, 21, 22).
124
Data Analysis
Power and cordance values from the baseline QEEG record-
ing were examined to test for differences in any brain region
among the four outcome groups, and no differences were found
(p>0.25 for power and cordance for all regions). Absolute and
relative power and cordance values for each brain region of in-
terest were therefore calculated for each subject as change from
baseline at the 2-, 4-, and 8-week QEEG recordings (the QEEG
value at the subsequent visit minus the baseline value). The ab-
solute power, relative power, and cordance data then were ana-
lyzed by using three separate repeated measures analyses of
variance (ANOVAs), with treatment response as the between-
group factor (medication responder, placebo responder, medi-
cation nonresponder, placebo nonresponder) and time as the
within-group factor (2 weeks, 4 weeks, and 8 weeks). The analy-
sis tested the hypothesis that there was no change in neurophys-
iologic brain function in depressed subjects over the course of 8
weeks of treatment with either antidepressant medication or
placebo by using a full-factorial model to test the response ef-
fect, the time effect, and the time-by-response interaction. The
equality of covariance matrices across groups was tested with
Box’s test statistic, which yielded a p value of 0.26, indicating
that the assumption of equality of covariance matrices was rea-
sonable. Where the main effect was significant, group differ-
ences were examined with a Bonferroni adjustment to control
for multiple comparisons.
Results
Clinical Outcome
Demographic and clinical characteristics of the subjects
(Table 1), as well as medication and placebo response
rates, final Hamilton depression scale scores (Table 3), and
dropout rates, were not significantly different between the
fluoxetine and venlafaxine trials. Because of the high de-
gree of comparability of the subjects and results from the
two trials, the data were pooled for analysis.
Overall, 52% of the subjects (13 of 25) receiving antide-
pressant medication responded to treatment, and 38% of
those receiving placebo (10 of 26) responded. Medication
responders and placebo responders could not be distin-
guished on the basis of their initial or final level of depres-
sion (Table 3). Pattern analysis revealed that a majority of
subjects in both responder groups had early and sustained
decreases in depression rating scores (seven of the 13 med-
ication responders and seven of the 10 placebo respond-
ers). Both responder groups had similar rates of decline in
depression scores (Figure 2) and ended with substantially
lower depression scores than nonresponders (the medica-
tion nonresponder and placebo nonresponder groups)
(Table 3).
QEEG Data
The repeated measures ANOVA revealed no differences
among groups in changes from baseline in relative or ab-
solute power values for any brain region (Table 4). Cor-
dance, however, showed a significant group effect for the
prefrontal region (Table 4). The within-group effect and
the interaction for this region were not significant, nor
were there any differences for any other brain region.
Am J Psychiatry 159:1, January 2002
 LEUCHTER, COOK, WITTE, ET AL.

TABLE 3. Characteristics of Responders and Nonresponders to Antidepressant Medication and to Placebo in a Quantitative
EEG Studya
Medication Placebo Medication Placebo
Characteristic Responders (N=13) Responders (N=10) Nonresponders (N=12) Nonresponders (N=16)
Mean SD Mean SD Mean SD Mean SD

Age (years) 41.2 11.7 38.2 15.2 42.3 13.2 43.2 9.6
Hamilton Depression Rating Scale score
Baseline 21.5 3.0 20.7 3.3 23.3 4.3 22.6 3.6
Final (week 8)b 6.0 3.1 6.1 3.4 18.4 4.6 17.9 4.5
Total number of depressive episodes 1.9 0.9 2.2 1.4 2.6 1.7 1.9 0.7

Ratio Ratio Ratio Ratio

Gender (male:female) 0.3:1 1.5:1 0.5:1 0.6:1

Family history of depression (positive:negative) 1.2:1 1.3:1 2.7:1 2:1
a Subjects were patients with major depressive episode enrolled in one of two 9-week double-blind, placebo-controlled treatment studies con-
ducted independently over a 24-month period. Active medications were fluoxetine, 20 mg/day, and venlafaxine, 150 mg/day.
b Significant difference between responders (to either medication or placebo) and nonresponders (to either medication or placebo) (F=121.4,
df=1, 49, p<0.0001).

There was no effect of time on the cordance or relative FIGURE 2. Mean Hamilton Depression Rating Scale Scores
power measures. Absolute power for the left temporal re- at Quantitative EEG Testing Sessions Over an 8-Week Study
Period in Responders and Nonresponders to Antidepres-
gion differed across time, although not by treatment re- sant Medication and to Placeboa
sponse status (Table 4).
The group average brain maps for these subjects (Figure 30
Placebo nonresponders (N=16)
3) confirmed that the major differences among the groups Score on Hamilton Depression Scale Placebo responders (N=10)
were seen in the prefrontal region. Although changes were Medication nonresponders (N=12)
seen in other brain regions at some time points, these Medication responders (N=13)
were not as marked or as consistent over time as were the 20
prefrontal changes. The changes in the prefrontal region,
as well as several other regions, appeared to be more
prominent over the right hemisphere.
The mean changes from baseline in prefrontal cordance 10
for all groups over time are shown in Figure 4. At week 2, the
medication responder subjects showed a unique and signif-
icant decrease in prefrontal cordance that differentiated
them from the three other groups (none of which showed a 0
decrease). This decrease appeared to resolve partly at weeks
Ho e

ks

ks

ks
urs

ee
48 selin

4 and 8 (Figure 4). At week 2, all other groups of subjects

ee

ee

ee
1W

2W

4W

8W
Ba

showed slight increases in prefrontal cordance that were

significantly different from the pattern for the medication
responders, although not a significant change from the re-
spective group baseline values. At week 4, this increase
achieved significance in the placebo responders, who dif-
fered both from their group baseline and from the medica-
tion responders. The difference became more marked at
week 8, when the placebo responders showed a further in-
crease above their group baseline that differed significantly
from both the medication responders and the medication
nonresponders (Figure 4). The placebo responders were
the only group showing prefrontal activity that increased
significantly over the baseline value. The medication non-
responders and placebo nonresponders showed no signifi-
cant change from their baseline values at any time point.
Discussion
To our knowledge, this is the first study that has com-
pared subjects treated with placebo and antidepressant
Testing Session
a There were no differences at any time point between the mean
scores of the medication responders and placebo responders, al-
though scores for both groups of responders were significantly dif-
ferent from those for both nonresponder groups at all time points
(p<0.05) except baseline.
medication and documented brain functional changes
during treatment in both groups. This study demonstrates
that although the symptomatic improvement resulting
from placebo and medication treatment may be similar,
the two treatments are not physiologically equivalent.
Both treatments affect prefrontal brain function, but they
have distinct effects and time courses.
These findings showing decreased prefrontal cordance
in depressed subjects responding to antidepressant medi-
cations are consistent with previous research showing de-
creased prefrontal metabolism or perfusion in treatment
responders, regardless of the medication or treatment mo-

Am J Psychiatry 159:1, January 2002 125

PLACEBO EFFECTS

TABLE 4. Effects of Treatment Response and Time on Quantitative EEG Cordance, Relative Power, and Absolute Power
Measures for Major Brain Functional Areas in Depressed Subjects Treated in Placebo-Controlled Antidepressant Trials (N=51)
Analysis by Wilks’s Lambdaa
Measure Effect of Treatment Response Effect of Time (Baseline or Week 8) Response-by-Time Interaction
and Brain Area F (df=3, 43) p F (df=2, 42) p F (df=6, 84) p
Cordanceb
Prefrontal 10.11 0.00004 0.53 0.58 1.82 0.11
Central 1.36 0.27 0.81 0.45 2.02 0.07
Temporal
Left 0.03 0.99 0.89 0.42 0.89 0.42
Right 0.59 0.63 0.53 0.59 0.77 0.60
Parietal
Left 1.50 0.24 0.26 0.77 1.19 0.32
Right 0.63 0.60 1.35 0.27 1.39 0.23
Occipital 0.52 0.67 0.52 0.60 1.92 0.09
Relative powerc
Prefrontal 0.13 0.94 0.73 0.49 0.69 0.65
Central 0.30 0.82 1.47 0.24 1.04 0.40
Temporal
Left 0.09 0.97 0.03 0.97 0.51 0.80
Right 0.45 0.72 0.58 0.57 0.59 0.74
Parietal
Left 0.17 0.92 0.51 0.60 0.81 0.57
Right 0.15 0.93 0.80 0.45 0.44 0.60
Occipital 0.27 0.85 0.89 0.42 0.78 0.59
Absolute powerd
Prefrontal 0.06 0.98 1.18 0.32 0.80 0.53
Central 0.20 0.90 1.06 0.36 1.26 0.29
Temporal
Left 0.82 0.49 3.31 0.05 1.26 0.28
Right 0.48 0.69 1.57 0.22 1.38 0.23
Parietal
Left 0.28 0.84 3.05 0.06 1.78 0.11
Right 0.50 0.69 1.21 0.12 1.15 0.34
Occipital 1.24 0.31 2.46 0.10 1.87 0.10
a Effect refers to the source of variance between groups (response or nonresponse to either medication or placebo), variance within groups
(time: baseline or week 8), and the interaction of response and time.
b Calculated by using a three-step algorithm that normalizes power across both electrode sites and frequency bands.
c The intensity of energy in a frequency band in microvolts squared.
d The percentage of the total energy from all bands concentrated in a single band.

dality examined (e.g., ECT) (8–12). The fact that the pla-
cebo responders showed an increase in prefrontal cor-
dance and that the medication responders showed a
decrease may help to explain some of the previously ob-
served heterogeneity in PET studies of patients treated for
depression. Although most studies of depressed patients
have shown that prefrontal metabolism and/or perfusion
decrease in response to successful treatment, several have
reported increases in metabolism or perfusion after treat-
ment response (23, 24). The current results suggest that
higher levels of perfusion or metabolism during treatment
for depression may be associated with a placebo response.
None of the previous studies included a placebo control,
so it is not possible directly to compare metabolism in pla-
cebo responder and medication responder groups. Fur-
thermore, the previous studies did not report information
on the pattern of change in symptoms, which might be
helpful in distinguishing placebo responders from medi-
cation responders.
Few clinical characteristics can be used to distinguish
placebo responders from medication responders. Placebo
responders are slightly more likely to have mild depressive
symptoms and to have been depressed a relatively short
period of time (25, 26). None of these features has suffi-
cient discriminating power to be useful clinically. The
most robust clinical predictor of a placebo response is the
time course of improvement in symptoms. Quitkin and
colleagues (27) have shown that early, abrupt, or nonper-
sistent responses are characteristic of response to placebo.
Subjects who improved during medication treatment but
who had the characteristic placebo pattern of response
were more likely to suffer a relapse of symptoms during
short-term or continuation treatment (2, 28, 29). The re-
sults of this study are not consistent with the results of pat-
tern analysis. In this study, the placebo responders were
slightly but not significantly more likely than the medica-
tion responders to show an early response to treatment,
and both groups showed symptom improvement that was
well sustained. The differences between our results and
those of Quitkin and colleagues could reflect the particu-
lar characteristics of our subject population. In any case,
the similarity of the clinical response patterns of placebo
responders and medication responders suggests that the
brain functional differences cannot be attributed solely to
group differences in the time-course or persistence of
symptom improvement.

126 Am J Psychiatry 159:1, January 2002

 LEUCHTER, COOK, WITTE, ET AL.

FIGURE 3. Change in Quantitative EEG Cordance From Baseline to Weeks 2, 4, and 8 in Responders and Nonresponders to
Antidepressant Medication and to Placeboa

Change From Baseline

2 Weeks 4 Weeks 8 Weeks
1.50

Placebo Responders
(N=10)
1.25

1.00

0.75
Medication Responders

0.50
(N=13)

Cordance Magnitude Change

0.25

0.0
Placebo Nonresponders

–0.25
(N=16)

–0.50

–0.75
Medication Nonresponders

–1.00
(N=12)

–1.25

–1.50

a Cordance maps showing the head as viewed from above, with the prefrontal regions at the top of each map. Yellow indicates no change,
green-blue indicates a decrease from baseline, and orange-red indicates an increase.

The current results are consistent with previous stud-
ies that found differences in brain function between pla-
cebo responders and medication responders. A meta-
analysis suggested that nonsuppressors on the dexa-
methasone suppression test were less likely to respond to
placebo (30). One study recently examined brain chemis-
try by using magnetic resonance spectroscopy in sub-
jects showing either the placebo or true-drug patterns of
response (as defined by Quitkin and colleagues) during
fluoxetine treatment (31). This study found that subjects
with the placebo pattern showed a decrease in the cho-
line-creatine ratio in the basal ganglia over time, while
those with the true-drug pattern showed an increase in
this ratio.
The finding of brain functional changes during “effec-
tive” placebo treatment, which are distinct from those as-
sociated with effective medication treatment, cast doubt
on two commonly held beliefs about placebo treatment.
First, administration of an inert pill (in the setting of a re-
search study) appears to be an active treatment, rather
than the no-treatment comparison it has been thought to
provide. Brain physiology was significantly altered in the
placebo responder group, not only in comparison to this
group’s baseline state, but also in comparison to medica-

Am J Psychiatry 159:1, January 2002 127

PLACEBO EFFECTS
FIGURE 4. Change in Quantitative EEG Cordance From Base-
line to Weeks 2, 4, and 8 in the Prefrontal Region of Re-
sponders and Nonresponders to Antidepressant Medication
and to Placebo
1.5
Placebo nonresponders (N=16)
Placebo responders (N=10)
Medication nonresponders (N=12)
Medication responders (N=13)
1.0
Change in Prefrontal Cordance
b cebo response, concluded that “it is difficult to distinguish
b
0.5
0.0
–0.5
–1.0
a,b
–1.5
Baseline Week 2
a Significant difference from baseline (t=–3.37, df=12, p=0.006).
b Placebo responders, medication nonresponders, and placebo non-
responders significantly different from medication responders (F=
8.50, df=3, 45, p<0.0001).
c Placebo responders significantly different from medication re-
sponders; medication responders significantly different from med-
ication nonresponders (F=5.11, df=3, 45, p=0.004).
d Significant difference from baseline at week 4 (t=–4.05, df=9, p=
0.004) and week 8 (t=–5.22, df=9, p=0.001).
e Placebo responders significantly different from medication re-
sponders and medication nonresponders (F=6.41, df=3, 45, p=
0.001).
tion responder, medication nonresponder, and placebo
nonresponder groups.
Second, these results suggest that a placebo response is
not functionally equivalent to an active drug response.
Brain physiology in placebo responders was altered in a
different manner than in the medication responders. Pla-
cebo responders showed a change in prefrontal cordance
that differed both in direction and in time course from the
change in the medication responders. This qualitative dif-
ference casts in a new light the assertion that 50%–75% of
antidepressant drug effect consists of a placebo effect (2),
since symptom improvement was not associated with a
similar physiologic alteration in the medication responder
and placebo responder groups. It is important to note,
however, that these data do not prove a causal link be-
tween brain functional changes and the therapeutic effect
of either medication or placebo. Further studies examin-
ing brain function in other conditions, including both no-
128
treatment and psychotherapy conditions, would be neces-
sary to elucidate the degree and type of functional change
that may be uniquely associated with medication and
placebo.
The current results indicate the value of studies moni-
d,e toring brain function in placebo-treated patients, since
such studies may reveal novel physiologic mechanisms
underlying symptom improvement. One recent meta-an-
c,d alytic study, which disputed the significance of the pla-
c
between reporting bias and a true effect of placebo on
b
subjective outcomes” (32). Brain functional measures may
e in fact provide a valuable physiologic evaluation of the na-
ture and significance of apparent placebo responses. True
placebo responses may be these that are associated with
singular changes in prefrontal function.
Since placebo and active medication may have distinct
d,e
mechanisms of action, it would be important to deter-
mine if any outcome differences are associated with these
different mechanisms. Future studies that use brain func-
tional measures should characterize multiple dimensions
c
of the nature of improvement in placebo-treated patients,
including longer-term follow-up of mood symptoms and
other dimensions of improvement (e.g., quality of life and
functional status measures). The results of this study, if
Week 4 Week 8
replicated, suggest a role for cordance or other brain func-
Time tional measurements in effectiveness studies of prospec-
tive antidepressant agents. Future studies using func-
tional imaging may help both to distinguish the effects of
antidepressant medication from those of placebo and to
elucidate the mechanisms through which placebo treat-
ment ameliorates depressive symptoms.
Received March 20, 2000; revisions received March 26 and July 5,
2001; accepted Aug. 28, 2001. From the Quantitative EEG Labora-
tory, UCLA Neuropsychiatric Institute and Hospital; and the Division
of Adult Psychiatry, Department of Psychiatry and Biobehavioral Sci-
ences, UCLA School of Medicine, Los Angeles. Address reprint re-
quests to Dr. Leuchter, UCLA Neuropsychiatric Institute, 760 West-
wood Plaza, Los Angeles, CA 90024-1759; afl@ucla.edu (e-mail).
Supported by Research Scientist Development Award MH-01165
and grant MH-40705 from NIMH to Dr. Leuchter and by a Young In-
vestigator Award from the National Alliance for Research in Schizo-
phrenia and Depression and Career Development Award MH-01483
from NIMH to Dr. Cook. The authors acknowledge the grant support
of Eli Lilly and Company, Inc. and Wyeth-Ayerst Laboratories, Inc. in
conducting this study.
References
1. Shapiro AK, Shapiro E: The Powerful Placebo: From Ancient
Priest to Modern Physician. Baltimore, Johns Hopkins Univer-
sity Press, 1997
2. Quitkin FM: Placebos, drug effects, and study design: a clini-
cian’s guide. Am J Psychiatry 1999; 156:829–836
3. Kirsch I, Sapirstein G: Listening to Prozac and hearing placebo:
a meta-analysis of antidepressant medication. Prevention and
Treatment article 2a, posted July 28, 1998. http://jour-
nals.apa.org/prevention/volume1/pre0010002a.html
4. Kirsch I: Specifying nonspecifics: psychological mechanisms of
placebo effects, in The Placebo Effect: An Interdisciplinary Ex-
Am J Psychiatry 159:1, January 2002

ploration. Edited by Harrington A. Cambridge, Mass, Harvard
University Press, 1999, pp 166–186
5. Enserlink M: Psychopharmacology: can the placebo be the
cure? Science 1999; 284:238–240
6. Quitkin FM, Stewart JW, McGrath PJ: Columbia atypical depres-
sion: a subgroup of depressives with better response to MAOI
than to tricyclic antidepressants or placebo. Br J Psychiatry
1993; 163:30–34
7. Stewart JW, Quitkin FM, McGrath PJ, Amsterdam J, Fava MD,
Fawcett J, Reimherr F, Rosenbaum J, Beasley C, Roback P: Use
of pattern analysis to predict differential relapse of remitted
patients with major depression during one year of treatment
with fluoxetine or placebo. Arch Gen Psychiatry 1998; 55:334–
343
8. Drevets WC, Raichle ME: Neuroanatomical circuits in depres-
sion: implications for treatment mechanisms. Psychopharma-
col Bull 1992; 28:261–274
9. Drevets WC, Price JL, Simpson JR Jr, Todd RD, Reich T, Vannier
M, Raichle ME: Subgenual prefrontal cortex abnormalities in
mood disorders. Nature 1997; 386:824–827
10. Brody AL, Saxena S, Stoessel P, Gillies LA, Fairbanks LA, Albor-
zian S, Phelps ME, Huang S-C, Wu H-M, Ho ML, Ho MK, Au SC,
Maidment K, Baxter LR: Regional brain metabolic changes in
patients with major depression treated with either paroxetine
or interpersonal therapy: preliminary findings. Arch Gen Psy-
chiatry 2001; 58:631–640
11. Nobler MS, Sackeim HA, Prohovnik I: Regional cerebral blood
flow in mood disorders, III: treatment and clinical response.
Arch Gen Psychiatry 1994; 51:884–897
12. Nobler MS, Sackeim HA, Louie J, Prohovnik I, Roose SP, Van
Heertum R: Clinical response to antidepressants is associated
with reduced frontal CBF in late-life depression, in 1998 An-
nual Meeting New Research Program and Abstracts. Washing-
ton, DC, American Psychiatric Association, 1998, p 168
13. Leuchter AF, Uijtdehaage SH, Cook IA, O’Hara R, Mandelkern
M: Relationship between brain activity and cortical perfusion
in normal subjects. Psychiatry Res Neuroimaging 1999; 90:
125–140
14. Cook IA, Leuchter AF, Uijtdehaage SHJ, Osato S, Holschneider
DH, Abrams M, Rosenberg-Thompson S: Altered cerebral en-
ergy utilization in late life depression. J Affect Disord 1998; 49:
89–99
15. Leuchter AF, Cook IA, Uijtdehaage SHJ, Lufkin RB, Anderson-
Hanley C, Abrams M, Rosenberg-Thompson S, O’Hara R, Simon
SL, Babaie AB: Brain structure and function and the outcomes
of treatment for depression. J Clin Psychiatry 1997; 58(suppl
16):22–31
16. Hamilton M: A rating scale for depression. J Neurol Neurosurg
Psychiatry 1960; 23:56–62
17. Cook IA, Leuchter AF, Witte E, Abrams M, Uijtdehaage SHJ,
Stubbeman W, Rosenberg-Thompson S, Anderson-Hanley C:
Neurophysiologic predictors of treatment response to fluoxe-
tine in major depression. Psychiatry Res 1999; 85:263–273
18. Cook IA, O’Hara R, Uijtdehaage S, Mandelkern M, Leuchter AF:
Assessing the accuracy of topographic EEG mapping for deter-
Am J Psychiatry 159:1, January 2002
LEUCHTER, COOK, WITTE, ET AL.
mining local brain function. Electroencephalogr Clin Neuro-
physiol 1998; 107:404–414
19. Leuchter AF, Newton TF, Cook IA, Walter DO, Rosenberg-
Thompson S, Lachenbruch PA: Changes in brain functional
connectivity in Alzheimer’s-type and infarct dementia. Brain
1992; 115:1543–1561
20. Brenner RP, Ulrich RF, Reynolds CF: EEG spectral findings in
healthy elderly men and women: sex differences. Electroen-
cephalogr Clin Neurophysiol 1995; 94:1–5
21. Ulrich G, Haug HJ, Fahndrich E: Acute versus chronic EEG ef-
fects in maprotiline- and in clomipramine-treated depressive
inpatients and the prediction of therapeutic outcome. J Affect
Disord 1994; 32:213–217
22. Ulrich G, Renfordt E, Zeller G, Frick K: Interrelation between
change in the EEG and psychopathology under pharmacother-
apy for endogenous depression: a contribution to the predic-
tor question. Pharmacopsychiatry 1984; 17:178–183
23. Baxter LR, Phelps ME, Mazziotta JC: Cerebral metabolic rates
for glucose in mood disorders: studies with positron emission
tomography and fluorodeoxyglucose F18. Arch Gen Psychiatry
1985; 42:441–447
24. Sackeim HA, Prohovnik I: Brain imaging studies of depressive
disorders, in The Biology of Depressive Disorders, Part A: A Sys-
tems Perspective. Edited by Mann JJ, Kupfer DJ. New York, Ple-
num, 1993, pp 205–258
25. Wilcox C, Cohn J, Linden R, Heiser J, Lucas P, Morgan DL, De-
Francisco D: Predictors of placebo response: a retrospective
analysis. Psychopharmacol Bull 1992; 28:157–162
26. Khan A, Brown WA: Who should receive antidepressants: sug-
gestions from placebo treatment. Psychopharmacol Bull 1991;
27:271–274
27. Quitkin FM, Rabkin JG, McGrath PJ, Stewart JW, Harrison W, Ross
DC, Tricamo E, Fleiss J, Markowitz J, Klein DF: Heterogeneity of
clinical response during placebo treatment. Am J Psychiatry
1991; 148:193–196
28. Quitkin FM, McGrath PJ, Rabkin JG, Stewart JW, Harrison W, Ross
DC, Tricamo E, Fleiss J, Markowitz J, Klein DF: Different types of
placebo response in patients receiving antidepressants. Am J
Psychiatry 1991; 148:197–203
29. Quitkin FM, McGrath PJ, Stewart JW, Ocepek-Welikson K, Taylor
BP, Nunes E, Delivannides D, Agosti V, Donovan SJ, Ross D, Pet-
kova E, Klein DF: Placebo run-in period in studies of depressive
disorders. Br J Psychiatry 1998; 173:242–248
30. Ribeiro SC, Tandon R, Grunhaus L, Greden JF: The DST as a pre-
dictor of outcome in depression: a meta-analysis. Am J Psychi-
atry 1993; 150:1618–1629
31. Sonawalla SB, Renshaw PF, Moore CM, Alpert JE, Nierenberg
AA, Rosenbaum JF, Fava M: Compounds containing cytosolic
choline in the basal ganglia: a potential biological marker of
true drug response to fluoxetine. Am J Psychiatry 1999; 156:
1638–1640
32. Hrobjartsson A, Gotzsche PC: Is the placebo powerless? an
analysis of clinical trials comparing placebo treatment with no
treatment. N Engl J Med 2001; 344:1594–1602; correction,
345:304
129